Kaufman is often praised for being deeply imaginative and original: Being John Malkovich stars John Malkovich as a fictional version of himself; Human Nature is mostly told in flashback; Adaptation tells the story of Kaufman himself, trying to write the film the viewer is watching and to understand the book from which it is adapted with the help of his twin brother Donald Kaufman (credited as a co-writer despite being a fictional character); Eternal Sunshine of the Spotless Mind mainly takes place in the mind of the main character while his memory is erased; and Synecdoche, New York is a postmodern film with many complex non-realistic elements.

After high school graduation, Kaufman attended Boston University before transferring to New York University where he studied film. While attending New York University, Kaufman met Paul Proch, who he would write many unproduced scripts and play with.[3]

Between 1983 and 1984, Kaufman and Proch wrote comedic articles and spoofs on spec for National Lampoon. His work included parodies of Kurt Vonnegut and the X-Men.[4] Kaufman and Proch tried to get their screenplays produced, sending them to many people in film industry. The only response the two ever received for their work was a supportive letter from Alan Arkin in regards to their screenplay titled Purely Coincidental.[5] In hope of finding talent agents the two began to write spec scripts for television series such as Married... With Children and Newhart. In 1991, Kaufman moved from Minneapolis to Los Angeles in search of more job prospects. Kaufman got his start in television by writing two episodes for Chris Elliott's Get a Life during the 1991–1992 season.[3] During the 1993–1994 season, Kaufman worked on Fox's sketch comedy show The Edge. Kaufman wrote some pilot scripts while working as a television writer, but none of them were produced.[3] He later worked as a writer for Ned and Stacey and The Dana Carvey Show.[6]

He first came to mainstream notice as the writer of Being John Malkovich, directed by Spike Jonze, earning an Academy Award nomination for his effort and winning a BAFTA. He wrote the script on spec in 1994, sending it to many companies and studios, all turning it down. The script eventually reached Francis Ford Coppola, who passed it on to his then-son-in-law Jonze, who agreed to direct the film[7]

After the success of Being John Malkovich, another one of Kaufman's screenplays was produced titled Human Nature, which was directed by Michel Gondry and produced by Kaufman and Jonze.

Kaufman and Jonze reunited yet again as the director screenwriter respectively for Adaptation, which earned him another Academy Award nomination and his second BAFTA. Adaptation featured a fictionalized version of Kaufman and his fictional brother, Donald, who is credited as writer of the film along with Kaufman. The idea came to Kaufman while attempting to adapt Susan Orlean novel The Orchid Thief into film. Struggling with writer's block, Kaufman turned the script into an exaggerated account of his struggles with adapting the screenplay.[8]

Kaufman wrote the screenplay for Confessions of a Dangerous Mind, a biopic based on the "unauthorized autobiography" of Chuck Barris, the creator of such popular game shows as The Dating Game and host of The Gong Show. The film focuses on Barris's claim to have been a CIAhit man. It was George Clooney's directorial debut. Kaufman criticized Clooney for making drastic alterations to the script without consulting him (instead, Clooney consulted Barris). Kaufman said in an interview with William Arnold: "The usual thing for a writer is to deliver a script and then disappear. That's not for me. I want to be involved from beginning to end. And these directors [Gondry and Jonze] know that, and respect it."[9]

After agreeing to participate in Carter Burwell's Theater of the New Ear, a double bill "sound play", Kaufman wrote and directed the audio play Hope Leaves the Theater, while the other play in the production, titled Sawbones, was written and directed by the Coen Brothers[11]Theater of the New Ear debuted in April 2005 at St. Ann's Warehouse in Brooklyn, New York.[12] Due to scheduling conflicts, later productions of Theater of the New Ear did not feature the Coen's play, replacing it with Anomalisa which was written by Kaufman under the pseudonym "'Francis Fregoli".[13]

Kaufman made his directorial film debut with the postmodern film Synecdoche, New York.[14] It premiered at the Cannes Film Festival in 2008. The idea for the film came when Kaufman and Spike Jonze were approached to direct a horror film. Rather than make a conventional horror film, the two agreed to have the film deal with things they found frightening in real life, rather than typical horror film tropes.[15] Kaufman decided to direct the film after Jonze left the project as the director to direct Where the Wild Things Are instead.

Kaufman was slated to write and direct a film with the working title Frank or Francis. Few details have been confirmed about the plot except that it is a musical comedy about internet anger culture.[16] In July 2012, Jack Black, who was to star in the film, revealed in an interview that funding for the project had fallen through, as the studio was unsure about its chances for success after the financial failure of Kaufman's last directorial effort. The future of the project is uncertain.

Dino Stamatopoulos, a former colleague of Kaufman's from The Dana Carvey Show, became interested in adapting Kaufman's Anomalisa play script into a stop motionanimated film. With Kaufman's permission, Stamatopoulos turned to the crowdfunding website Kickstarter in order to fund the film. The Kickstarter page for the film was set up in August 2012 and by the time funding had ended $406,237 was pledged.[17] It is premiering at the 2015 Toronto International Film Festival in Semptember of 2015.

Trying to make a return to television, Kaufman directed and wrote a pilot for FX titled How and Why in 2014. The plot was described as being about a "man who can explain how and why a nuclear reactor works but is clueless about life". FX decided to not pick up the pilot, but it has been shopped to other outlets.[18]

Apes recur in Kaufman's work: in Being John Malkovich Lotte has a pet chimp named Elijah, in Human Nature Puff was raised as an ape, in Confessions of a Dangerous Mind Penny dreams about an ape, and in Adaptation the original deus ex machina was a swamp ape.[20]